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In Clinical Shiga Toxin-Producing Escherichia Coli Isolates toxins Article Molecular Characterization of the Enterohemolysin Gene (ehxA) in Clinical Shiga Toxin-Producing Escherichia coli Isolates Ying Hua 1,2, Ji Zhang 3, Cecilia Jernberg 4, Milan Chromek 5 , Sverker Hansson 6,7, Anne Frykman 6,7, Yanwen Xiong 8 , Chengsong Wan 1, Andreas Matussek 2,9,10,11,* and Xiangning Bai 8,12,* 1 Department of Microbiology, School of Public Health, Southern Medical University, Guangzhou 510515, China; [email protected] (Y.H.); [email protected] (C.W.) 2 Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, 141 52 Stockholm, Sweden 3 Molecular Epidemiology and Public Health Laboratory, School of Veterinary Sciences, Massey University, Palmerston North 4100, New Zealand; [email protected] 4 The Public Health Agency of Sweden, 171 82 Solna, Sweden; [email protected] 5 Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet and Karolinska University Hospital, 141 86 Stockholm, Sweden; [email protected] 6 Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden; [email protected] (S.H.); [email protected] (A.F.) 7 Department of Pediatrics, Department of Pediatrics, Sahlgrenska Academy, Sahlgrenska Academy, University of Gothenburg, 416 85 Gothenburg, Sweden 8 State Key Laboratory of Infectious Disease Prevention and Control, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China; [email protected] 9 Laboratory Medicine, Jönköping Region County, Department of Clinical and Experimental Medicine, Linköping University, 551 85 Jönköping, Sweden 10 Oslo University Hospital, 0372 Oslo, Norway Citation: Hua, Y.; Zhang, J.; Jernberg, 11 Division of Laboratory Medicine, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway C.; Chromek, M.; Hansson, S.; 12 Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Frykman, A.; Xiong, Y.; Wan, C.; 141 86 Stockholm, Sweden Matussek, A.; Bai, X. Molecular * Correspondence: [email protected] (A.M.); [email protected] (X.B.) Characterization of the Enterohemolysin Gene (ehxA) in Abstract: Shiga toxin (Stx)-producing Escherichia coli (STEC) is an important foodborne pathogen Clinical Shiga Toxin-Producing with the ability to cause bloody diarrhea (BD) and hemolytic uremic syndrome (HUS). Little is known Escherichia coli Isolates. Toxins 2021, about enterohemolysin-encoded by ehxA. Here we investigated the prevalence and diversity of ehxA 13, 71. https://doi.org/10.3390/ in 239 STEC isolates from human clinical samples. In total, 199 out of 239 isolates (83.26%) were ehxA toxins13010071 positive, and ehxA was significantly overrepresented in isolates carrying stx2a + stx2c (p < 0.001) and eae (p < 0.001). The presence of ehxA was significantly associated with BD and serotype O157:H7. Five Received: 15 December 2020 Accepted: 15 January 2021 ehxA subtypes were identified, among which, ehxA subtypes B, C, and F were overrepresented in Published: 19 January 2021 eae-positive isolates. All O157:H7 isolates carried ehxA subtype B, which was related to BD and HUS. Three ehxA groups were observed in the phylogenetic analysis, namely, group I (ehxA subtype A), Publisher’s Note: MDPI stays neutral group II (ehxA subtype B, C, and F), and group III (ehxA subtype D). Most BD- and HUS-associated with regard to jurisdictional claims in isolates were clustered into ehxA group II, while ehxA group I was associated with non-bloody stool published maps and institutional affil- and individuals ≥10 years of age. The presence of ehxA + eae and ehxA + eae + stx2 was significantly iations. associated with HUS and O157:H7 isolates. In summary, this study showed a high prevalence and the considerable genetic diversity of ehxA among clinical STEC isolates. The ehxA genotypes (subtype B and phylogenetic group II) could be used as risk predictors, as they were associated with severe clinical symptoms, such as BD and HUS. Furthermore, ehxA, together with stx and eae, can be used as Copyright: © 2021 by the authors. a risk predictor for HUS in STEC infections. Licensee MDPI, Basel, Switzerland. This article is an open access article Keywords: Shiga toxin-producing Escherichia coli; enterohemolysin; ehxA; gene diversity; hemolytic distributed under the terms and uremic syndrome; clinical significance conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Toxins 2021, 13, 71. https://doi.org/10.3390/toxins13010071 https://www.mdpi.com/journal/toxins Toxins 2021, 13, 71 2 of 11 Key Contribution: This study showed a high prevalence and considerable genetic diversity of enterohemolysin-encoding gene ehxA among clinical STEC isolates. The ehxA genotypes could be used as risk predictors, ehxA subtype B and phylogenetic group II were found to be associated with severe clinical symptoms, such as bloody diarrhea (BD) and hemolytic uremic syndrome (HUS). 1. Introduction Shiga toxin-producing Escherichia coli (STEC) is an important enteric foodborne pathogen that can cause bloody diarrhea (BD), hemorrhagic colitis, and potentially fatal hemolytic uremic syndrome (HUS) in infected humans [1]. STEC is estimated to cause 2.8 million cases of enteric disease in humans per year globally [2]. Over 400 STEC serotypes have been identified, among which, O157:H7 is the most prevalent serotype and is linked to severe human illness, such as HUS [3,4]. Nevertheless, since the early 2010s, non-O157 STEC, especially the so-called “top six” serogroups (O26, O45, O103, O111, O121, and O145), have been associated with continuously increasing numbers of STEC outbreaks and may account for up to 80% of STEC infections [2,5,6]. Humans are infected through contact with infected animals or the consumption of STEC-contaminated water, vegetables, milk, or meat. Shiga toxins (Stx1 and Stx2) are the main virulence factors of STEC, which can mediate a significant cytotoxic effect in human vascular endothelial cells [7]. stx genes are located in the genomes of Shiga-toxin-converting bacteriophages [8]. At least 15 stx1 and stx2 gene subtypes have been identified, among which, stx2a, stx2c, and stx2d are more virulent than other subtypes as they are highly associated with severe clinical outcomes, such as HUS [9]. Besides Stx, eae-encoding intimin, which is responsible for the intimate adherence of STEC, is also a significant virulence trait of pathogenic STEC [10,11]. In addition, hemolysin-encoding genes have been regarded as STEC virulence markers [7]. So far, four different types of hemolysins have been identified, namely, alpha-hemolysin (hlyA), silent hemolysin (sheA), bacteriophage-associated enterohemolysin (e-hlyA), and plasmid-carried enterohemolysin (ehxA)[12]. Enterohemolysin displays hemolytic activity that enables STEC to be observed on washed sheep blood agar, which is commonly used as a phenotypic indicator of STEC strains [13,14]. It is noteworthy that ehxA is prevalent in STEC strains and is closely associated with isolates causing diarrheal disease and HUS [15]. Enterohemolysin belongs to the repeats in toxin (RTX) family, which has a pore- forming capacity [16]. ehxA is located on a large virulence plasmid and its nucleic acid sequence has about 3000 base pairs [17]. The presence of ehxA has a close association with stx, thus it is proposed as an epidemiological marker for the rapid characterization of STEC strains [13]. For example, in the U.S. Food and Drug Administration E. coli Identification (FDA-ECID) microarray, ehxA is included as one of the genetic markers for the rapid characterization of STEC isolates [18]. Six genetically distinct ehxA subtypes (A to F) have been described in E. coli by using PCR in combination with restriction fragment length polymorphism (RFLP) analysis [12]. STEC ehxA subtypes differ significantly among strains isolated from different sources. Subtypes A and C are mostly found in animal isolates, where subtype A is detected in food-associated strains and subtype C is commonly found in clinical strains [12]. However, such data are limited; the correlation between ehxA subtypes and strains sources, as well as the clinical relevance, remains to be further elucidated. A recent study in Sweden showed that almost all of the eae-positive isolates, except one, harbored ehxA, and the coexistence of ehxA and eae was shown to be associated with BD [19]. In a previous study, only 10.9% of isolates carried eae among 138 ehxA-positive non-O157 STEC isolates from human, animal, and food sources in China, and 61.54% of these were clinically relevant [20]. The aim of this study was to investigate the prevalence and genetic diversity of the ehxA gene, its correlation with serotypes, and the presence of stx and eae. Furthermore, we aimed to assess the association between ehxA subtypes and disease severity. Toxins 2021, 13, 71 3 of 11 2. Results 2.1. Distribution of ehxA in the Clinical STEC Isolates Among the 239 STEC strains isolated in Sweden, ehxA was identified in 199 (83.26%) isolates. Fifty-three (26.63%) of the ehxA-positive isolates were from patients with HUS, 47 (23.62%) were from patients with BD, and 99 (49.75%) were from individuals with NBS (non-bloody stool). All O157:H7 isolates were ehxA positive and the majority (45/65, 69.23%) were also stx2a + stx2c positive. The majority of the eae-positive STEC isolates (166 of 173, 95.95%)
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